Imageable biopsy site marker

ABSTRACT

A biopsy site marker having at least one small marker body or pellet of bioresorbable material such as gelatin, collagen, polylactic acid, polyglycolic acid which has a radiopaque object, preferably with a non-biological configuration. The at least one bioresorbable body or pellet with a radiopaque object is deposited into the biopsy site, by an delivery device that includes an elongated tubular body with a piston slidable within the tubular body. One end of the tube is placed into the biopsy site. At least one but preferably several marker bodies or pellets are deposited sequentially into the biopsy site through the tube. At least the bioresorbable materials of the detectable markers remain present in sufficient quantity to permit detection and location of the biopsy site at a first time point (e.g., 2 weeks) after introduction but clear from the biopsy site or otherwise do not interfere with imaging of tissues adjacent the biopsy site at a second time point (e.g., 5-7 months) after introduction.

RELATED APPLICATIONS

This application is a continuation of application Ser. No. 10/719,448,filed on Nov. 21, 2003, which is a continuation of application Ser. No.10/684,124, filed on Oct. 10, 2003, which is a continuation ofapplication Ser. No. 10/001,043, filed on Oct. 31, 2001 (now U.S. Pat.No. 6,347,241), which is a continuation of application Ser. No.09/343,975 (now U.S. Pat. No. 6,662,041), filed on Jun. 30, 1999, and acontinuation-in-part application to application Ser. No. 09/241,936,filed on Feb. 2, 1999, now U.S. Pat. No. 6,161,034, which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention is in the field of markers to be employed atbiopsy sites to permanently mark the site, and to methods and apparatusfor applying the permanent marker. More particularly, the presentinvention relates to a marker that is optimally adapted for markingbiopsy sites in human breast tissue with permanently placed markers thatare detectable by X-ray.

BACKGROUND OF THE INVENTION

In modern medical practice small tissue samples, known as biopsyspecimens, are often removed from tumors, lesions, organs, muscles andother tissues of the body. The removal of tissue samples may beaccomplished by open surgical technique, or through the use of aspecialized biopsy instruments such as a biopsy needle. A well knownstate-of-the-art instrument that is often used in connection with thepractice of the present invention is known as the “vacuum assisted largecore biopsy device”.

After a tissue sample has been removed, it is typically subjected todiagnostic tests or examinations to determine cytology, histology,presence or absence of chemical substances that act as indicators fordisease states, or the presence of bacteria or other microbes. The abovementioned and other diagnostic tests and examinations per se are wellknown in the art and need not be described here. It is sufficient tonote that the information obtained from these diagnostic tests and/orexaminations is often of vital importance for the well-being of thepatient and is used to make or confirm diagnoses and often to formulatetreatment plans for the patient. As is known, obtaining a tissue sampleby biopsy and the subsequent examination are frequently, almostinvariably, employed in the diagnosis of cancers and other malignanttumors, or to confirm that a suspected lesion or tumor is not malignant,and are frequently used to devise a plan for the appropriate surgicalprocedure or other course of treatment.

Examination of tissue samples taken by biopsy, often by theabove-mentioned “vacuum assisted large core biopsy sampler” is ofparticular significance in the diagnosis and treatment of breast cancerwhich is the most common cancer suffered by women in the U.S.A andelsewhere in the industrially developed world. Proper diagnosticprocedures, frequent examination by well known techniques such as“mammography” and prompt subsequent surgical treatment have, however,significantly reduced the mortality rate caused by this form of cancer.For this reason, in the ensuing discussion of the pertinent backgroundart and in the ensuing description the invention will be described asused for marking biopsy sites in human and other mammalian breast,although the invention is suitable for marking biopsy sites in otherparts of the human and other mammalian body as well.

Thus, as is known, when an abnormal mass in the breast is found byphysical examination or mammography a biopsy procedure follows almostinvariably. The nature of the biopsy procedure depends on severalfactors. Generally speaking, if a solid mass or lesion in the breast islarge enough to be palpable (i.e., felt by probing with the fingertips)then a tissue specimen can be removed from the mass by a variety oftechniques, including but not limited to open surgical biopsy or atechnique known as Fine Needle Aspiration Biopsy (FNAB). In opensurgical biopsy, an incision is made and a quantity of tissue is removedfrom the mass for subsequent histopathological examination. In the FNABprocedure, a small sample of cells is aspirated from the mass through aneedle and the aspirated cells are then subjected to cytologicalexamination.

If a solid mass of the breast is small and non-palpable (e.g., the typetypically discovered through mammography), a relatively new biopsyprocedure known as “stereotactic needle biopsy” may be used. Inperforming a stereotactic needle biopsy of a breast, the patient lies ona special biopsy table with her breast compressed between the plates ofa mammography apparatus and two separate digital x-rays are taken fromtwo slightly different points of view. A computer calculates the exactposition of the lesion with X and Y coordinates as well as depth of thelesion within the breast. Thereafter, a mechanical stereotacticapparatus is programed with the coordinates and depth informationcalculated by the computer, and such apparatus is used to preciselyadvance the biopsy needle into the small lesion. Usually at least fiveseparate biopsy specimens are obtained from locations around the smalllesion as well as one from the center of the lesion.

After the biopsy sample is taken, it may take several days or even aweek before the results of the examination of the sample are obtained,and still longer before an appropriate treatment decision is reached. Ifthe decision involves surgery it is clearly important for the surgeon tofind the location in the breast from where the tumor tissue has beentaken in the biopsy procedure, so that the entire tumor and possiblysurrounding healthy tissue can be removed. For example, the particulartreatment plan for a given patient may require the surgeon to remove thetumor tissue and 1 centimeter of the tissue surrounding the tumor. Aco-pending application for United States Letters Patent by the sameinventors discloses markers which are particularly well adapted formarking biopsy sites in the human breast, and which markers remaindetectable by X-ray, ultrasound or some other detection technique onlyfor a given time period (i.e. for 6 months) and slowly disappearthereafter, for example by absorption into the body. The purpose of suchmarkers is to facilitate the surgical procedure that is performed whilethe marker is still detectable. The disappearance of the marker after alonger period of time may be advantageous to avoid obscuring orinterfering with follow-up studies or further mammography or otherimaging studies.

In connection with the background art the following specific printed artis mentioned. U.S. Pat. Nos. 2,192,270 and 5,147,307 describe visuallydiscernible markers that are applied externally to the patient's skin.Radiographically (X-ray) detectable tissue markers (e.g., clips orstaples) that are attached to tissue adjacent to the site from which thebiopsy specimen has been removed, are described in International PatentPublication No. WO 98/06346. Radiographically visible markers (e.g.marker wires) that may be introduced into the biopsy site and areinserted through the biopsy needle after a tissue sample is removed andwhich are thereafter allowed to remain protruding from the patient'sbody, are also described in WO 98/06346. However, due to the consistencyof breast tissue and the fact that these biopsy site markers aretypically introduced while the breast is still compressed between themammography plates, these biopsy markers of the prior art may becomeattached to adjacent bands of connective tissue that do not remain atthe specific location of the biopsy after the breast has beendecompressed and removed from the mammography apparatus, and may sufferfrom additional disadvantages as well.

Thus, there is still a need in the art for of biopsy site markers thatare deliverable into the cavity created by removal of the biopsyspecimen and not into tissue that is located outside of that biopsycavity, and which will not migrate from the biopsy cavity even when thebreast tissue is moved, manipulated or decompressed. Moreover, suchdesired markers should remain detectable at the biopsy site i. e. withinthe biopsy cavity for an indefinite time period, and still should notinterfere with imaging of the biopsy site and adjacent tissues at alater point of time, and most importantly should be readilydistinguishable in the various imaging procedures from lines ofcalcifications which frequently are signs for a developing malignancy.The present invention provides such permanent biopsy site markers aswell as apparatus and method for delivering such markers into the biopsycavity.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a biopsy site markerthat is deliverable into the cavity created by removal of the biopsyspecimen.

It is another object of the present invention to provide a biopsy sitemarker that does not migrate from the biopsy cavity even when thesurrounding tissue is moved, manipulated or decompressed.

It is still another object of the present invention to provide a biopsysite marker that meets the foregoing requirements and that remainsdetectable at the biopsy site for an indefinite period of time.

It is yet another object of the present invention to provide a biopsysite marker that meets the foregoing requirements and that is readilydistinguishable by X-ray from granules or lines of calcifications whichfrequently are signs for a developing malignancy.

It is a further object of the present invention to provide an apparatusand method for placing into the biopsy cavity a biopsy site marker thatmeets the foregoing requirements.

These and other objects and advantages are attained by a biopsy sitemarker that comprises small bodies or pellets of gelatin which enclosesubstantially in their interior a radio (X-ray) opaque object. Thegelatin pellets are deposited into the biopsy site, typically acylindrical opening in the tissue created by the recent use of a vacuumassisted large core biopsy device, by injection from an applicatorthrough a tube that is placed into the biopsy site. Typically, severalgelatin pellets, only some of which typically do, but all of which maycontain the radio opaque object, are deposited sequentially from theapplicator into the site through the tube. The radio opaque objectscontained in the gelatin bodies have a non-biological shape orconfiguration to be identifiable as a man-made object such that inobservation by typical mammography equipment, that is when viewed fromat least two different viewing angles, they do not assume the shape of aline, whereby they are readily distinguishable from granules or lines ofcalcification.

The present invention also provides chemical preparations and methodsfor marking biopsy sites, whereby a detectable marker (i.e., a substanceor article that is detectable by imaging and/or palpation and/orvisualization) is introduced into the cavity created by removal of abiopsy specimen (e.g., the “biopsy cavity”) such that (i) the markerwill remain present and detectable at the biopsy at a first time point(e.g. 2 weeks after introduction), and (ii) the marker will clearsufficiently from the biopsy site, or will otherwise be undetectable byimaging so as not to interfere with follow-up imaging of the biopsy siteand adjacent tissues at a second time point (e.g. typically 5-8 monthsand preferably at about 6 months after introduction).

A. Types of Markers

(i) Imageable Embodiments of the Marker

In embodiments of the invention wherein the marker is detectable byimaging, it will typically be imageable by a suitable imaging means orapparatus. For example, the marker may be radiographically visible(e.g., more radiopaque or more radiolucent than the surrounding tissueso as to be imageable by x-ray, CT scan, mammography, fluoroscopy, orother roentgenological means. In other imageable embodiments, the markermay be imageable by other means such as magnetic resonance imaging(MRI), ultrasound, Doppler, or other presently known or hereafterinvented imaging techniques.

(ii) Palpable Embodiments of the Marker

In embodiments of the invention wherein the marker is detectable bypalpation, the marker will comprise a space occupying substance orobject(s) that, when introduced into the cavity created by the removalof the biopsy specimen, will form a palpable mass that can be located byclosed palpation of the breast and/or by local palpation by a surgeonduring dissection of the surrounding breast tissue. Space occupyingmarkers that are palpable include balloon(s), beads, microspheres, offlowable bulking materials such as collagen.

(iii) Visually Discernible Embodiments of the Marker

In embodiments of the invention wherein the marker is visuallydetectable, the marker will comprise a substance or object(s) that is ofa color that is different from the color of breast tissue and blood suchthat, when introduced into the cavity created by the removal of thebiopsy specimen, the marker will be visually detectable by a surgeonduring dissection of the surrounding breast tissue.

(iv) Energy-Emitting Embodiments of the Marker

In some embodiments of the invention, the marker may emit energy that isdetectable by a suitable detection apparatus. For example, the markermay comprise a radioactive substance that is detectable by way of agamma detector, scintillation counter or other apparatus for detectingradiation. Similarly, the marker may comprise a signal emittingapparatus (e.g. a transmitter or transponder) that will continuously, oroccasionally when interrogated by ultrasound or other type ofinterrogating energy, emit a signal (e.g., radiofrequency, ultrasound,etc.) that can be detected by an apparatus that is useable to detectthat particular type of signal.

(v) Marker Embodiments That Are Detectable by More Than One DetectionMeans

In some embodiments of the invention, the detectable marker may bedetectable by a combination of any two or more of the above-summarizedimaging, visual, palpation and/or emission/detection techniques. Forexample, an imageable marker of the present invention may additionallycomprise a palpable component as described above (e.g., a spaceoccupying material or article) so as to render the marker both imageableand palpable after implantation at the biopsy site. Alternatively, animageable marker of the present invention may additionally be providedwith a visible component as described above (e.g., a colored substanceor article) so as to render the marker both imageable and visuallydiscernible after implantation at the biopsy site. Similarly, by way ofillustrative example, an imageable marker of the present invention mayadditionally comprise a palpable component as described above (e.g., aspace occupying material or article) and a visible component asdescribed above (e.g., a colored substance or article) so as to renderthe marker imageable, palpable and visible during surgery.

B. Consistency and Properties of the Marker

(i) Substantially Insoluble Marker Substances

In accordance with the invention, the detectable marker may comprise asubstance (e.g., a gas, lipid, oil, powder, suspension or slurry) thatmay be delivered into the cavity formed by removal of a biopsy sample(i.e., the “biopsy cavity”), and which has solubility and/orbiodistributive properties that allow it to remain present anddetectable (e.g., imageable, palpable, energy-emitting and/or visible)at the biopsy site until at least the first predetermined time point(e.g., at least 2 weeks after introduction), but which will allow thesubstance to be substantially cleared (e.g., dissolved, distributed fromor locally metabolized) from the biopsy site at the second predeterminedtime point (e.g., 6 weeks after introduction).

(ii) Soluble Marker Substances with Clearance Delaying Element(s)

Further in accordance with the invention, the detectable marker maycomprise a) a detectable (e.g., imageable, palpable, energy-emittingand/or visible) substance that, if delivered alone into the cavityformed by removal of the biopsy specimen, would clear from such biopsycavity so as to be no longer detectable at the first predetermined timepoint (e.g., two (2) weeks after introduction) in combination with b) aclearance limiting element (e.g., a diffusion-limiting polymer matrix, amembrane or liposomal encapsulation, a biodegradable matrix orencapsulant, etc . . . ) that will limit the dissolution,biodistribution and/or local metabolism of the detectable substance toremain present and detectable at the biopsy site for at least 2 weeksafter introduction, but which will allow the detectable substance to besubstantially cleared (e.g., dissolved, distributed from or locallymetabolized) from the biopsy site at the second predetermined time point(e.g., 5-8 months and preferably at about 6 months after introduction).

(iii) Markers That Do No Interfer With Subsequent Imaging Studies

Still further in accordance with the invention, the detectable markermay comprise a substance or article that is detectable by a detectionmethod that is different from the imaging method that is intended to beused for follow-up imaging of the biopsy site and adjacent tissues, thusallowing the marker to reside at the biopsy site beyond the second timepoint (i.e., that time point at which follow-up imaging studies are tobe conducted) or even indefinitely, without interfering with suchfollow-up imaging studies. For example, the marker may be detectable bypalpation, visualization and/or ultrasound but not visible on x-ray,thereby allowing for follow-up x-ray studies without interference by themarker while remaining locatable by palpation, visualization,specialized detection and/or ultrasound in the event that a surgeon,radiologist or other practitioner may wish to subsequently locate thebiopsy site.

-   -   (iv) Markers That Adhere to the Wall(s) of the Biopsy Cavity

Still further in accordance with the invention, the detectable marker ofthe present invention may comprise, or may be combined with, an adhesivewhich will cause the detectable marker to adhere to tissue immediatelyadjacent the void created by removal of the biopsy sample.

C. Methods for Using Biopsy Site Markers of the Present Invention

Still further in accordance with the invention, there are providedmethods for surgical excision of tissue that is located adjacent to orsurrounding a biopsy cavity in which a visually detectable marker of thepresent invention has been delivered. The method generally comprises thesteps of a) visualizing the perimeter of the visually discernible markerand b) excising tissue that lies adjacent to the perimeter of saidvisually discernible marker. This method of surgical excision may beused to accurately excise and remove a quantity of tissue of a specificwidth (e.g., a region or band that is 2 centimeters wide) that surroundsor lies adjacent to the original biopsy cavity. Because the biopsy sitemarkers of the present invention actually occupy the original biopsycavity, they serve to accurately mark the perimeter of that biopsycavity. As such, the surgeon is able to accurately visualize theboundary of the biopsy cavity and to then excise and remove tissue thatlies within a certain distance (e.g., 2 centimeters) of that cavityboundary. Such visualization of the biopsy cavity boundary may be madeeasier or enhanced when the biopsy site marker comprises, in addition toa visually discernible component such as a dye or carbon particles, aspace-occupying bulking agent as described above in reference topalpable embodiments of the invention as the presence of such spaceoccupying or bulking agent may serve to dilate or distend the biopsycavity, thereby making it easier for the surgeon to visualize theboundaries of that biopsy cavity. This surgical excision method may beparticularly suitable in cases where the histopathological evaluation ofthe biopsy specimen suggests that additional cancerous cells maycontinue to reside in tissue located within a certain distance of theoriginal biopsy cavity boundary.

The features of the present invention can be best understood togetherwith further objects and advantages by reference to the followingdescription, taken in connection with the accompanying drawings, whereinlike numerals indicate like parts.

Additional objects, embodiments and advantages of the present inventionwill become apparent to those of skill in the relevant art upon readingand understanding of the following detailed description of preferredembodiments and the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a preferred embodiment of the biopsysite marker of the present invention.

FIG. 2 is a perspective view of a plurality of biopsy site markers inaccordance with the first embodiment of the present invention.

FIG. 3 is a perspective view of an applicator apparatus in accordancewith the present invention, for depositing the biopsy site marker at abiopsy site.

FIG. 4 is a perspective view of the applicator apparatus of FIG. 3,showing the applicator with an extended piston indicating that theapplicator is loaded with biopsy site markers.

FIG. 5 is a cross-sectional view of the site marker shown in FIG. 4, thecross section taken on lines 5-5 of FIG. 4.

FIG. 6 is an enlarged cross sectional view showing the applicator ofFIG. 4 loaded with biopsy site markers in accordance with the presentinvention.

FIG. 7 is a schematic view of a human breast, showing a biopsy cavity ofthe type obtained by a vacuum assisted large core biopsy sampler, intowhich a plurality of biopsy markers are deposited in accordance with thepresent invention.

FIG. 8 is a perspective view of a human breast having a lesion fromwhich a biopsy specimen has been removed, and showing a syringe andintroduction cannula operatively positioned for introduction of adetectable marker of the present invention into the cavity created byremoval of the biopsy specimen.

FIG. 8 a is an enlarged perspective view of a portion of the breast ofFIG. 8 after the detectable marker has been introduced and after thesyringe and introduction cannulas have been removed.

FIGS. 9 a-9 g are schematic, step-by-step showings of a preferred methodfor using a detectable marker of the present invention to mark the siteof a lesion that has been biopsied while the breast is compressed withina mammography apparatus.

FIG. 10 a is a schematic showing of a first embodiment of a detectablemarker of the present invention after introduction into a biopsy site.

FIG. 10 b is a schematic showing of a second embodiment of a detectablemarker of the present invention after introduction into a biopsy site.

FIG. 10 c is a schematic showing of a third embodiment of a detectablemarker of the present invention after introduction into a biopsy site.

FIG. 11 is a longitudinal sectional view of an injector device that isuseable to introduce a solid (e.g., powdered, particulate or granular)marker substance of the present invention into a biopsy site.

FIGS. 12 a-12 c are showings of a preferred method of excising andremoving tissue that lies within a predetermined zone located on allsides or only one side of the boundary of a previously-created biopsycavity.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The following specification taken in conjunction with the drawings setsforth the preferred embodiments of the present invention. Theembodiments of the invention disclosed herein are the best modescontemplated by the inventors for carrying out their invention in acommercial environment, although it should be understood that variousmodifications can be accomplished within the parameters of the presentinvention.

Referring now to the drawing figures and particularly to FIGS. 1 and 2,a body 20 of gelatin or reconstituted collagen in the shape of a pelletthat includes or incorporates a radio-opaque marker 22 of a definiteshape is disclosed. The gelatin or reconstituted collagen body 20 can beof virtually any shape or configuration, however the herein shown shapeof a cylinder or pellet is preferred. The gelatin body of pellet 20 isof such size that several of the pellets can be deposited in a biopsysite, such as a typical biopsy site obtained by using the vacuumassisted large core biopsy device that is frequently used in currentmedical practice. The gelatin body or pellet 20 is stored and isapplied, that is deposited in the biopsy site, in a dehydrated formthrough an applicator device that forms another aspect of thisinvention. However, when the gelatin body or pellet 20 of the inventionis not deposited through the applicator device, it does not necessarilyneed to be stored and applied in a dehydrated form. Nevertheless,storing the gelatin pellets 20 in dehydrated form increases their usefulshelf-life and renders it easier to keep them sterile.

After having been deposited at the biopsy site the gelatin marker 20slowly absorbs moisture from the surrounding tissue and becomeshydrated. In the dehydrated form, shown in the appended drawing figures,the gelatin body or pellet 20 is approximately 1 to 3 mm in diameter andis approximately 5 to 10 mm long. The presently preferred embodiment ofthe gelatin pellet 20 is approximately 2 mm in diameter and isapproximately 8 mm long. After the pellet 20 has reached hydrationequilibrium with the surrounding tissue it becomes approximately 3 to 5mm in diameter and approximately 10 to 15 mm long. After hydration thepresently preferred embodiment of the pellet 20 is approximately 4 mm indiameter and approximately 10 mm long.

The gelatin or reconstituted collagen material itself is observed underultrasound examination as a white spot because of the air pocketsusually entrapped in its matrix. In mammography the gelatin is observedas dark spots in normal breast, because of the presence of the airpockets. In a fatty breast viewed by mammography the gelatin marker isobserved as a lighter area containing dark spots, due to the water inthe hydrated gelatin absorbing more energy than the surrounding matrixand the air pockets within the matrix. A pellet 20 or plurality ofpellets 20 due to their bulk may also be palpable and locatable bytactile means within the breast tissue or other tissue. The gelatin orreconstituted collagen marker itself can be made even more radio-opaqueby ion-impregnation and chelation techniques which are described indetail in the aforesaid co-pending application Ser. No. 09/241,936 filedon Feb. 2, 1999 by the same inventors in connection with the descriptionof biopsy markers of that application, and the description of thismethod of rendering the gelatin markers radio-opaque is also providedhere below. The disclosure of co-pending application Ser. No. 09/241,936is incorporated herein by reference in its entirety. The gelatin orreconstituted collagen material can also be made more radio-translucentby entrapping (mixing) a substantial amount of air in the gelatin.Moreover, a visually detectable substance, such as carbon particles, ora suitable dye (e.g. methylene blue or indigo) may also be added to thegelatin to make the marker visible by a surgeon during dissection of thesurrounding breast tissue.

The gelatin or reconstituted collagen per se does not serve as apermanent marker of the biopsy site because it is eventually reabsorbedby the body, although the dye or even ionic material that made thegelatin visible or radio-opaque, respectively, may remain at the sitefor longer time period than the palpable gelatin pellet, and may remainthere indefinitely. Factors which influence how long the gelatin orreconstituted collagen pellet remains at the site, and various means toadjust this time period are described in the aforementioned co-pendingapplication Ser. No. 09/241,936.

It is a novel and important aspect of the present invention toincorporate into the gelatin or reconstituted collagen body or pellet 20the radio-opaque marker 22. The radio-opaque or X-ray detectable marker22 that is incorporated or enclosed in the gelatin pellet 20 must havethe following properties. First, by its very nature it must bedetectable by X-ray, including the type of radiography used in thepractice of mammography. It must be comprised of a material orcomposition that is not absorbed by the body and stays for indefinitetime at the biopsy site, retains its shape and remains X-ray detectableat the biopsy site also for an indefinite time. The material orcomposition of the radio-opaque marker 22 must, of course, bebiocompatible at the site where it is deposited. Another importantrequirement is that the biocompatible marker must have an identifiablespecific non-biological shape or form. The purpose of specific form forthe marker is to render the marker distinguishable under X-ray or in amammographic examination from naturally formed calcification granules ora line of such granules, which are also X-ray opaque. As is known, aline of calcification which normally forms along ducts is considered asign of developing malignancy. Thus, the marker 22 should be of suchspecific configuration that when it is viewed sterically, as during amammography examination, it should be distinguishable from an X-rayopaque line. Numerous specific shapes or configurations satisfy theforegoing requirements, however amorphous X-ray opaque material thatwould be uniformly (or substantially uniformly) distributed in thegelatin pellet 20 is unlikely to satisfy these requirements.

Materials or compositions which are suitable for the marker 22 includemetal, such as stainless steel, tantalum, titanium, gold, platinum,palladium, various alloys that are normally used in bioprosthesis andceramics and metal oxides that can be compressed into specific shapes orconfigurations. Among these the use of biocompatible metals is presentlypreferred, and the herein described preferred embodiment of the marker22 is made of stainless steel. Generally speaking the marker 22 isapproximately 0.01 to 0.06 inches wide, approximately 0.03 to 0.2 inchlong and approximately 0.002 to 0.02 inch thick. The presently preferredpermanent marker 22 shown in the drawing figures has the configurationor shape approximating an upside down turned Greek letter gamma, isapproximately 0.10 inch long and approximately 0.04 inch wide. Theupside-down Greek letter gamma shape is believed to be unique, has someresemblance to the popular breast cancer awareness ribbon and is readilydistinguishable under X-ray and mammography as a “man-made” markerobject from any naturally formed X-ray opaque body. Variousmanufacturing techniques which per se are well known in the art, can beutilized to manufacture the X-ray opaque permanent marker 22. Thus, themarker 22 can be formed from wire, or can be electrochemically etched orlaser cut from metal plates. The presently preferred embodiment of thegamma shaped marker 22 is formed by electrochemical etching fromstainless steel plates.

FIGS. 1, 2 and the other drawing figures, as applicable, show only onemarker in the gelatin pellet 20, although more than marker may beincorporated in the pellet 20. FIG. 1 discloses a cylindrically shapedgelatin pellet 20 that in accordance with the present invention includesthe gamma shaped stainless marker 22, and as an optional feature alsoincludes a dye or other coloring material (e.g. indigo) that also stayssubstantially permanently at the biopsy site and is visible by a surgeonwhen the breast tissue is dissected, as in an operation where tumortissue is removed (lumpectomy). Gelatin bodies or pellets 20 all ofwhich include one or more permanent radio opaque markers 22 inaccordance with the present invention may be deposited at a biopsy site.Alternatively, a series of gelatin bodies or pellets 20 where only somebut not all include a permanent X-ray opaque marker 22 of uniquenon-biological shape, may be deposited at the biopsy site. Preferably, aseries of pellets 20 are deposited where each second, each third, oreach fourth etc., pellet includes the marker 22. FIG. 2 discloses anexample of a series or sequence of pellets 20 where each second pellet20 includes the metal marker 22 and where each pellet 20 that does notinclude the metal marker 22 includes carbon black or dye that is visibleto the surgeon during operation. In this connection it should beunderstood and appreciated that as noted above the gelatin bodies orpellets 20 themselves serve a purpose of marking the biopsy site for apredetermined length of time, that is until they become absorbed by thebody.

The drawing figures, particularly FIGS. 1 and 2 show the metal marker 22disposed substantially in the center of the cylindrical gelatin pellet20. This is preferred but is not necessary for the present invention.The metal marker 22 can be embodied in or included in the gelatin body20 virtually anywhere. The gelatin body or pellet 20 however has to havesufficient integrity or firmness to retain the metal marker 22 and airbubbles which are usually deliberately entrapped in the gelatin. As isknown, the firmness or bodily integrity of gelatin is measured in unitsof Bloom. Generally speaking it was found in accordance with the presentinvention that the higher the Bloom strength of the gelatin used in themarker 20 the better the marker performs. The higher Bloom strengthgelatin holds gas bubbles within its matrix better than lower Bloomstrength gelatin. Gelatin with a Bloom strength of approximately 150especially 175 is adequate for the practice of the present invention,but a more preferred range is 200 to 300 Bloom, the most preferred rangebeing between 250 and 300. (For comparison, typical food gelatin isapproximately 75 Bloom, and gelatin of 300 Bloom feels like a softrubber eraser.)

A description how to obtain gelatin or reconstituted collagen bodiessuitable for use as markers 20 with various properties, before thepermanent radio-opaque metal or like marker 22 of specific form isincorporated therein, is provided below in connection with followingexamples.

Example of Radiographically Visible/Palpable Marker Material Formed ofMetal Ions in Combination With a Collagenous or Gelatinous Matrix

U.S. Pat. No. 4,847,049 (Yamamoto incorporated herein by reference)describes an ion-impregnation or chelation technique whereby an ion maybe impregnated or chelated to collagen for the purpose of impartingantimicrobial properties to the collagen preparation. Thus, using thistechnique, imageable ions such as radiographically visible metal ions,may be bound to a bulky collagenous material to form a marker 10 thatmay be a) imaged by radiographic means and b) located by palpation oftissue surrounding the biopsy site. For example, a silver ion-renaturedcollagen composition may be prepared by the following process:

Step 1—Renaturation of Collagen (or Gelatin)

Collagen may be renatured to an insoluble form by processing ofdenatured collagen that has been obtained from a natural source such asbovine corium (hide), bovine tendon, and porcine skin. Alternatively,pre-processed, insoluble collagen may be purchased in the form of acommercially available hemostatic material such as Collastat™ andAvitene™ nonwoven web. Methods for renaturing collagen are known in theliterature, including, for example, those methods described in U.S. Pat.Nos. 4,294,241 and 3,823,212. The specifications of U.S. Pat. Nos.4,294,241 and 3,823,212 are incorporated herein by reference.

A particularly preferred form of renatured collagen for utilization inaccordance with the present invention is one that has been renatured andcovalently cross-linked. This collagen may be prepared by utilizingreadily available polyfunctional cross linking agents or fixatives, suchas dialdehydes, dicarboxylic acids, diamines, and the like. Typically,tropocollagen is dissolved in a buffer of pH 3.0 to 5.0 to provide asolution containing approximately 1 to 2% by weight of the collagen.Then 1% of a dialdehyde cross-linking agent such as glutaraldehyde orformaldehyde is then added. The mixture is then frozen and stored forapproximately 24 hours. After thawing and washing to remove unreactedcross linking agent, the renatured cross-linked collagen is then readyfor contact with a silver ion-containing solution.

Step 2—Binding of Metal Ions to the Renatured Collagen

The source of silver ion may be a water soluble silver salt, preferablysilver nitrate. While the concentration of the silver ion in thesolution is not particularly critical, it will be usually convenient toutilize solutions in the concentration range of about 10 to 10millimolar.

The renatured collagen is preferably contacted with a silverion-containing solution in the pH range of about 4 to 9. The pH of thesilver ion-containing solution can be controlled by the addition of anappropriate titrating agent, such as nitric acid, or potassiumhydroxide, as required, to maintain the pH at less than about 9.0 toavoid the degradation of the silver. There is not believed to be anylower limit for the pH, however, normally a pH above 4.0 will beconvenient. A particularly preferred range for the pH is from 7.0 to7.5. The binding capacity of silver by collagen is particularlyeffective within this preferred pH range, although the amount of bindingby silver by the collagen is further controllable by the concentrationof the silver ion-containing solution and/or exposure time of thecollagen to the silver ion-containing solution. Simultaneous with orsubsequent to exposure of the collagen to the silver ion-containingsolution, the collagen is then exposed to ultraviolet radiation ofenergy and duration sufficient to strengthen the binding of the silverions to the collagen without substantial formation of metallic silverformed as a result of oxidation of various functional groups in thecollagen by the silver ion. While the exact limits of the ranges of theconditions which will be sufficient to strengthen the binding of thesilver ions without substantial formation of metallic silver are notprecisely determinable, it will generally suffice to maintain the pH ofthe silver-collagen environment at less than 8.0 while exposing thecollagen to ultraviolet radiation in the range of about 210 to 310 nmwavelength for about from 5 to 15 minutes. The time of UV exposure forcomplete reaction is inversely proportional to the light intensity whichis preferably in the range of 100 to 1,000 microwatts/cm². A slightcoloration of the collagen due to the exposure to ultraviolet radiationis acceptable, i.e., a turning from white to a light brown to yellowcolor, indicating a slight oxidation reaction occurring in the collagen,however, the radiation should not be to the extent that dark brown orblack areas in the collagen occur due to over-oxidation and/orsubstantial formation of metallic silver. Normally the exposure will beperformed at ambient temperatures, i.e., in the range of about 20° to25° C., however, there is not believed to be any reason why the exposurecould not occur at higher or lower temperatures providing that thetemperature is not high enough to cause degradation of the collagenand/or silver ion. There is not believed to be any lower limit to thetemperature at which the exposure may take place, provided it is abovethe freezing point of the ion-containing solution. Ultraviolet radiationmay be provided by any conventional ultraviolet radiation source ofappropriate wavelength, such as germicidal lamps and mercury/xenonlamps.

Step 3 (Optional)—Addition of Visible Component to Marker

If it is desired for the marker to be detectable visually, as well as byimaging and palpation, a quantity of a visible substance having a colordissimilar blood or tissue may be added. For example, carbon particlesor a dye (e.g., methylene blue, indigo) may be added to theabove-prepared silver ion/collagen preparation to provide a coloredsilver ion/collagen marker 10 that is imageable (by radiographic means),palpable (by hand) and visible (under white light in the operatingroom).

The above-described collagen-metal ion marker 10 (with or withoutvisible marker component) is introduced into the cavity created byremoval of the biopsy specimen. The quantity of this marker 10introduced may be sufficient to distend or stretch the biopsy cavitysomewhat, thereby creating a more palpable and obvious mass of markermaterial at the biopsy site.

Renatured gelatin or a cross-linked gelatin preparation such as Gelfoam™may be impregnated or combined with a metal ion to provide agelatin-metal ion marker material. The gelatin may be prepared andion-bound by the same method as set forth hereabove for collagen.

Example of Radiographically or Ultrasonically Visible/Palpable MarkerMaterial

Step 1—Renaturation of Collagen (or Gelatin)

Collagen or gelatin is renatured, as by the method described in Step 1of the immediately preceding example and described in the literature,including, for example, those methods described in U.S. Pat. Nos.4,294,241 and 3,823,212.

Step 2—Dispersing of Air or Other Gas in the Renatured Collagen orGelatin Matrix

Air or another biologically inert gas (e.g., carbon dioxide) is thendispersed throughout the renatured collagen or gelatin matrix by asuitable means such as mixing, mechanical blending, nucleation,bubbling, etc. This results in the formation of many small gas bubblesthroughout the collagenous or gelatinous matrix and provides a markersubstance that can be introduced into the biopsy cavity through acannula or tube and is substantially more radio-lucent than the tissuesurrounding the biopsy cavity. In this regard, this marker can be imagedby x-ray or ultrasound but will not block or obscure imaging of tissuethat lies immediately adjacent the biopsy cavity. Also, because of thebulk of the collagen or gelatin matrix, the marker is readily palpableand locatable by tactile means within the surrounding breast tissue orother tissue.

Step 3 (Optional)—Addition of Visible Marker Component

If it is desired for the marker to be detectable visually, as well as byimaging and palpation, a quantity of a visible substance having a colordissimilar to blood or tissue may be added. For example, carbonparticles or a dye (e.g., methylene blue, indigo) may be added to theabove-prepared silver ion/collagen preparation to provide a coloredsilver ion/collagen marker 10 that is imageable (by radiographic means),palpable (by hand) and visible (under white light in the operatingroom).

In routine use, the above-described collagen/gas or gelatin/gas marker10 (with or without visible marker component) is introduced into thecavity created by removal of the biopsy specimen. The quantity of thismarker 10 introduced may be sufficient to distend or stretch the biopsycavity somewhat, thereby creating a more palpable and obvious mass ofmarker material at the biopsy site.

Preferred Example of Preparing Cylindrically Shaped Gelatin Pellets 20Having a Colorant and Including the Permanent Marker

80 grams of dry gelatin obtained from porcine skin is mixed into 1000 mlof hot water (180° F.). Variations in gelatin to water ratio will changethe consistency but are nevertheless permissible within the scope of theinvention. The 80 grams of gelatin is about the maximum amount whichwill dissolve in water without modifications to pH. The gelatin is thenfully dissolved in the water with slight mixing. In a separatecontainer, 1.6 grams of indigo colorant is mixed into 20 ml of ethylalcohol. Then the ethanol solution of the colorant is added by mixing togelatin dissolved in water. Air is then whipped into gelatin mixture tofroth the mixture.

The gelatin dissolved in water is then poured into molds (not shown)which have the shape of the desired gelatin body. In the preferredembodiment the mold is shaped to provide the cylindrical pellet shown inthe drawing figures. One gamma (.gamma.) shaped permanent marker 22,made by chemical etching from stainless steel plates, is deposited intothe gelatin in each mold. (In alternative embodiments more than onemarker 22 may be deposited into each mold.) Due to the viscosity of thegelatin solution the marker 22 does not usually sink to the bottom ofthe mold. The top of the plate (not shown) holding a plurality of moldsis squeegeed to level the mixture.

After cooling to approximately 40° F. or cooler temperature the gelatinsets and provides the gelatin body 20 that incorporates the permanentmarker 22 However, in order to dehydrate the marker it is first frozenand thereafter lyophilized in commercial lyophilization apparatus.Gelatin pellets containing the permanent marker 22 but not having acolorant can be prepared in the same manner, but without adding indigodye or other colorant. Gelatin bodies or markers 20 that do not includeor incorporate a permanent marker 22 can also be made in this manner,but without depositing the marker 22 into the gelatin after it has beenplaced into the mold. The gelatin body 20 prepared in this manner isreabsorbed from the biopsy site by the human body in approximately threeweeks, whereas the permanent marker 22 remains indefinitely.

Description of the Applicator Apparatus and Its Use In Conjunction Withthe Biopsy Marker of the Invention

Referring now to FIGS. 3-7 the applicator device or apparatus 24 withwhich the biopsy markers of the invention are preferably applied ordeposited, is disclosed. In this connection it should be understood thatthe biopsy markers of the invention can be used without the applicator,and can be deposited in accordance with the various methods andtechniques utilized in the state-of-the-art. However, a preferredtechnique of applying the biopsy markers of the invention is to place ordeposit them in a biopsy cavity that is obtained with a vacuum assistedlarge core biopsy device of the type presently used in thestate-of-the-art. Such a device, distributed for example by Johnson andJohnson Endo Surgery is well known in the art, and is schematicallyshown in FIG. 7.

The applicator 24 of the invention comprises an elongated cylindricalbody 26 having an interior cavity and a piston 28 that fits and slidesback and forth in the elongated cylindrical body 26. The cylindricalbody 26 has an enlarged disk 30 at one end 32. The disk 30 serves torender it convenient for a user (not shown) to operate the applicator24, as is described below. The cylindrical body 26 that can also bedescribed as an elongated flexible tube has an opening 34 that commencesa relatively short distance, that is approximately 0.3 inch before itsother, closed end 36. The opening 34 is configured to form a ramp in theside of the tube 26. The outer diameter of the tube 26 is such that itfits through the vacuum assisted large core biopsy device 38 shown inFIG. 7. In this connection it should of course be understood that theprecise dimensions of the tube 26 are coordinated with the dimensions ofthe piston 28 and with the vacuum assisted large core biopsy device 38.Moreover, the diameter of the gelatin pellets 20 in their dehydratedform are also coordinated with the inner diameter of the cylinder ortube 26. The cylinder or tube 26 and the piston 28 can be made from anyappropriate medical grade plastic material, and is preferably made ofhigh density polyethylene. The outer diameter of the presently preferredembodiment of the cylinder or tube 26 is approximately 0.093 inch andits inner diameter is approximately 0.07 inch.

In the preferred manner of using the biopsy markers of the presentinvention having the permanent markers 22 incorporated in a gelatin body20, as well as using biopsy markers that have only the gelatin body 20without a permanent marker 22, the applicator device 24, more preciselythe tube 26 is loaded with a desired number of pellets 20, as is shownin FIGS. 4-6. Any number of pellets 20 within the range of 1 toapproximately 30 may be loaded within the tube 26, however presently itappears that approximately 8 pellets 20 are optimal for being loadedinto the tube 26 and to be deposited in a biopsy cavity whereapproximately 1 gram of tissue had been removed. Such a biopsy cavity 40in a human breast 42 is schematically illustrated in FIG. 7. The pellets20 which are loaded into the applicator tube 26 may all include thepermanent marker 22, but it is presently preferred that only every otherpellet 20 loaded into the applicator tube 26 have the permanent marker22. Such an array of 8 pellets 20, alternating between pellets with andwithout permanent markers 22 is shown in FIG. 2.

When the pellets 20 are in the tube 26 the piston 28 is extended, as isshown in FIGS. 4 and 5. The pellets 20 are expelled one-by-one from thetube 26 through the ramp-shaped opening 34 as the piston 28 is pushedinto the cylinder or tube 26. During this process the closed end 36 ofthe tube 26 is disposed in the cavity 40 formed by biopsy sampling. Itis contemplated that the dispersed radio-opaque permanent markers 22provide a good definition of the entire biopsy cavity 40 for subsequentobservation or surgical procedure. FIG. 3 illustrates the applicatordevice 24 after the pellets 20 have been expelled from the applicatortube 26.

FIGS. 8 and 8 a shows a human breast B which contains a lesion L, suchas a mass suspected to be cancerous. An outer cannula 52 has beeninserted percutaneously into the lesion L and a biopsy needle (notshown) has been passed through the outer cannula 52 and used to remove abiopsy specimen from the center of the lesion, thereby forming a biopsycavity BC within the lesion L. After removal of the biopsy needle (notshown), a marker introduction cannula 55 has been passed through theouter cannula such that its distal end 52 d is located within the biopsycavity BC. A device 54 for delivering a flowable, detectable marker 50of the present invention is attached to the proximal end 52 p of theintroduction cannula 55 and is being used to inject a quantity of thedetectable marker 50 into the biopsy cavity BC, as shown. FIGS. 9 a-9 g′are schematic, step by step showings of a preferred method for using adetectable marker 50 to mark the site of a lesion L that has beenbiopsied while the breast B is compressed within a mammography apparatus56 a and 56 b.

Properties and Functional Requirements of the Detectable Marker

Preferred Imageable and Instrument-Detectable Embodiments

The detectable markers 50 of the present invention may be visible on animage created by the particular type or imaging device(s) availableduring the procedure. In many cases, a form of roentgenographic imaging(e.g., mammography, x-ray, fluoroscopy, CT, etc.) will be used, and theimageable marker 50 will thus comprise a material that is more or lessradio-lucent or more or less radiopaque than the tissue surrounding thebiopsy cavity (e.g., air, other gas, lipid, oil, a metal salt, bariumpowder, etc.) such that the marker 50 can be imaged by such x-ray means.In other instances, ultrasound imaging may be used and the imageablemarker will comprise a material or substance that has differentultrasound reflective properties (and possible different radiographicdensity) than the body tissue surrounding the biopsy cavity BC (e.g.,air, carbon dioxide, other gasses, saline solution, other liquids, etc.)In other instances, a magnetic imaging technique such as magneticresonance imaging (MRI) may be used and the imageable marker 50 willcomprise a ferromagnetic material or material (e.g., iron powder) havingdifferent magnetic density than the body tissue surrounding the biopsycavity BC.

Similarly, the marker 50 may be a substance or article that emits energy(e.g., radiation) that is detectable by an instrument (e.g., a gammadetector).

Preferred Palpable Embodiments

The preferred palpable embodiments of the invention preferable comprisea substance (e.g., a collagen material as described in U.S. Pat. No.4,066,083) or an article (e.g., balloon(s), bead(s), etc.) that aresufficient mass to be palpated and located by tactile means whiledisposed within the biopsy site.

Preferred Visible Embodiments

The preferred visible embodiments of the invention may comprise acolored substance such as a dye or colorant (e.g., methylene blue,gentian violet, indigo, dyes used in tattooing, etc.) or colorantparticles (e.g., india, indigo, carbon particles or carbon preparationsdescribed in Langlois, S. L. P. and Carter, M. L., Carbon Localizationof Impalpable Mammographic Abnormalities, Australas Radiol. 35: 237-241(1991) and/or Svane, G. A Stereotaxis Technique for Preoperative Markingof Non-Palpable Breast Lesions, Acta Radiol. 24(2): 145-151 (1983).

Preferred Combination Embodiments

The markers 50 of this invention may combine the attributes of any ofthe imageable, palpable and/or visible embodiments to provide fordetection of the marker 50 by multiple means, such as a) imaging andpalpation, b) imaging and visualization, c) imaging, palpation andvisualization, or d) visualization and palpation.

Preferred Residence Time of the Marker at the Biopsy Site

The detectable markers 10 of the present invention are formulated and/orconstructed so as not to move or migrate from the biopsy site when thesurrounding tissue is flexed or reconfigured (e.g., as occurs when abreast is decompressed and removed from a mammography machine).Additionally, the detectable markers 10 are formulated and/orconstructed to (i) remain present at the site in sufficient quantity topermit imaging and location of the site for at least two (2) weeks afterintroduction and (ii) clear sufficiently from the site to permit imagingof tissue adjacent to the site, without interference from saiddetectable marker, at six (6) months after introduction.

Because the marker 50 is located at, and does not move or migrate from,the biopsy site it serves as a landmark that the surgeon may use tolocate and treat or remove the remaining portion of the lesion withouthaving to dissect and explore the surrounding tissue in attempting tolocate the lesion. This aspect of the invention is particularlybeneficial in cases (such as breast lumpectomy procedures) where it isdesired to surgically remove the lesion L with minimal disfigurement,scarring or change in architecture of the surrounding tissue.

Because the marker 50 remains detectable at the biopsy site for at leasttwo (2) weeks, the commencement of medical or surgical treatment of thelesion L may be delayed for up to two (2) weeks following the removal ofthe biopsy specimen and the marker 50 will still be present and useableto assist the treating surgeon or other physician in locating anddirecting treatment to the remaining portion of the lesion. This two (2)week minimum period of residence is especially beneficial in cases whereimmediate frozen sections can not be read by a pathologist, such ascases of suspected breast cancer wherein a small, non-palpable lesion ofthe breast has been biopsied by stereotactic biopsy, and the biopsyspecimen is sent for routine histopathological evaluation (e.g., fixing,staining and microscopic examination) which takes several days tocomplete.

Also, because the marker substantially clears from the biopsy sitewithin six (6) months after its introduction, it will not interfere withor obscure subsequent diagnostic imaging of any remaining portion of thelesion L or the surrounding tissue. This six (6) month maximum residencetime of the marker is especially beneficial in cases where the lesion isdetermined not to be cancerous at present, but presents a risk forfuture tumorigenesis that warrants periodic imaging of the site of thelesion L and surrounding tissue.

Embodiments Where the Properties of The Marker's Detectable ComponentAlone Result in Desired Residence Time

In some embodiments, the detectable marker 10 may comprise a detectablematerial that has pharmacokinetic properties (e.g., solubility,dissolution, potential for distribution from the biopsy site, potentialfor local metabolism or break down at the biopsy site) that cause it toremain present at the biopsy site in sufficient quantity to permitimaging of and location of the site for at least 2 weeks after itsintroduction, while clearing sufficiently from the site to permitimaging of tissue adjacent to the site without interference from saiddetectable marker, at 6 months after introduction.

In many applications of the invention, the particular pharmacokinetic orbiodistributive property(ies) that determine the rate at which themarker 10 clears from the biopsy site may include its solubility in theinterstitial fluids that are present at the biopsy site. In this regard,it has been determined that when the marker 50 is formed of detectablematerial having a solubility coefficient of less than 1−10⁻³ grams per100 cubic centimeters of water, such detectable material will typicallyhave the desired detectable residence time within the biopsy site of atleast two (2) weeks but not more than 5 to 7 months, and preferably notmore than about 6 months. However, it will be appreciated that thedetectable residence time of the marker 50 at the biopsy site willadditionally vary with the amount of marker 50 material that has beenintroduced in the biopsy cavity. In this regard, a large volume of amaterial having a relatively high solubility coefficient can beintroduced into the biopsy cavity to ensure that, even though thematerial has a relatively fast clearance rate, an imageable amount ofthe material will remain present at the biopsy site at the first timepoint (e.g., two (2) weeks). On the other hand, a relatively smallvolume of material having a low solubility coefficient may be introducedinto the biopsy cavity and, due to its slow clearance rate, will remainimageable at the biopsy site at the first time period (e.g., two (2)weeks).

Specific examples of radiographically visible materials that, ifintroduced into the biopsy site alone, would exhibit the desireddetectable residence time (i.e., at least 2 weeks but not more than 6weeks) include but are not necessarily limited to; AgCl; Agl; BaCO₃;BaSO₄; K; CaCO₄; ZnO; Al₂O₃; and the possible combinations thereof.

Embodiments With a Clearance Delaying Element to Provide the DesiredResidence Time

In other embodiments, the detectable marker 50 may comprise a detectablematerial that, if introduced into biopsy site alone, would clearsubstantially from the biopsy site in less than two (2) weeks after itsintroduction, thereby failing to provide the desired minimum detectableresidence time at the biopsy site of at least two (2) weeks. In suchembodiments, the detectable material will be combined (e.g., mixed with,encapsulated by, suspended in, etc.) a clearance delaying element thatwill cause the detectable material to remain present at the biopsy sitein sufficient quantity to permit imaging of and location of the site forat least 2 weeks after its introduction, while still allowing thedetectable material to clear sufficiently from the biopsy site to permitimaging of tissue adjacent to the site without interference from saiddetectable marker, at 6 weeks after introduction.

Examples of radiographically visible materials that would clear frommost biopsy sites in less than two (2) weeks include but are notnecessarily limited to; air, gas, lipid, oil, AgNO₃; ammonium salts;sodium salts; potassium salts; ethiodized oil (Ethiodol availablecommercially from Savage Laboratories, Mellville, N.Y., and certainradiographic contrast agents such as iohexol (Omnipaque, available fromNyegaard-Schering AG, available from Squibb/Bristol Myers.

Examples of clearance delaying elements that may be combined with thedetectable material to form a detectable marker of the present inventioninclude but are not necessarily limited to; polylactic acid;polyglycolic acid; polycapriolactone; an encapsulating membranesurrounding the detectable material.

The following examples are presently preferred formulations fordetectable markers 50 of this embodiment: Component Amount Formulation 1AgNO₃ 20-70 parts by weight Polylactic Acid 30-80 parts by weightFormulation 2 Ethiodol 10-50 parts by weight Polyglycolic Acid 50-90parts by weight Formulation 3 Ethiodol 10-70 parts by weight TopicalThrombin 30-90 parts by weight Formulation 4 Polylactic Acid 50-70 partsby weight Air 30-50 parts by weight

Form and Consistency of the Detectable Marker

FIGS. 10 a-10 c illustrate examples of the different possible forms orconsistencies of detectable markers 50 of the present invention.

Flowable Markers

FIG. 10 a shows an example of a detectable marker 50 a of a flowableconsistency that is injectable through the lumen of the introductioncannula 55 into the biopsy cavity BC formed within the lesion L.Typically, such flowable markers 50 a will comprise a dry powder,suspension, or solution. For example, a quantity of dry AgCl powder of10-1000 micron particle size may be passed through the introductioncannula 55.

FIG. 11 shows an example of an injector device 100 that is useable inplace of the introduction cannula 55, to introduce a solid (e.g.,powdered, particulate or granular) marker 50 of the present inventioninto a biopsy site. As shown, this device 60 comprises a non-taperedtubular barrel 61 having a substantially cylindrical inner wall 62 and aplunger 63 that is advanceable within the barrel 61. A quantity of asolid marker material of this invention is loaded into the barrel 61 ofthe device 60, the barrel 61 is inserted into the biopsy site, and theplunger 63 is advanced so as to expel the marker material out of thedistal end of the barrel 61 and into the biopsy site.

Plurality of Beads or Pellets

FIG. 10 b shows an example of an detectable marker 50 b that comprises aplurality of beads or pellets of approximately 10-1000 microns indiameter. Each bead or pellet may itself be formed of detectablematerial that is biodegradeable or otherwise clearable from the biopsysite so as to exhibit the desired detectable residence time as describedhereabove such as silver chloride or silver nitrate.

Alternatively, each bead or pellet may contain a detectable material inits interior and the outer surface of the bead or pellet may be a skinor encapsulating material that is biodegradable such as polylactic acid,so as to provide for the desired detectable residence time within thebiopsy site.

Beads or pellets filled with air, carbon dioxide, or other suitable gasmay be used as markers 50 b of the present invention that are detectableby either ultrasound or x-ray. However, even though such gas-filledmarkers 50 b of the present invention are visible on x-ray, they willnot obscure or block x-ray imaging of tissue adjacent to the biopsycavity and, thus, need not biodegrade or clear from the biopsy site bythe second time point (e.g., 5-7 months).

Inflatable Balloon

FIG. 10 c shows an example of a detectable marker 50 c that comprises aninflatable balloon. Such inflatable balloon is passed through theintroduction cannula and inflated within the biopsy cavity BC formedwithin the lesion L. The material of the balloon itself may bedetectable and biodegradable or otherwise clearable from the biopsy siteso as to exhibit the desired detectable residence time as describedhereabove. One example of such a material is polyurethane that has beensubjected to hydrolysis in situ. Alternatively, the balloon may containa detectable material and the balloon itself may form a skin orencapsulating material (e.g., polyurethane) that is biodegradeable so asto provide for the desired detectable residence time within the biopsysite.

Balloons filled with air, carbon dioxide, or other suitable gas may beused as markers 50 c of the present invention that are detectable byeither ultrasound or x-ray. However, even though such gas-filled markers50 c of the present invention are visible on x-ray, they will notobscure or block x-ray imaging of tissue adjacent to the biopsy cavityand, thus, need not biodegrade or clear from the biopsy site by thesecond time point (e.g., 5-7 months).

Optional Adhesive For Attaching the Marker to Tissue Adjacent the Site

In any of the above-described embodiments of the invention, the marker10 may have inherent adhesive properties, or the marker may furthercomprise an adhesive such as a polyurethane, polyacrylic compound,polyhydroxymethacrylate, fibrin glue (e.g., Tisseal™), collagenadhesive, or other biological or biocompatable adhesive that will causethe marker to adhere to tissue adjacent the biopsy cavity BC. Suchoptional adhesive will further ensure that the marker 10 does notmigrate or move from the biopsy site as tissue surrounding the site ismoved, flexed, compressed or decompressed.

Method for Surgical Excision of Tissue Located Adjacent a Biopsy Site

FIGS. 12 a-12 c show a preferred method for using a visually discerniblemarker 50 of the present invention to guide the excision and removal oftissues located within a specific band, region or location adjacent theboundaries of the biopsy cavity. As shown in FIG. 12 a, a visible marker50 has been introduced into the biopsy cavity BC so as to permitvisualization of the boundary BOU of the biopsy cavity BC by thesurgeon. Such visualization of the boundary BOU of this biopsy cavity BCcan enable the surgeon to selectively remove tissue that is locatedwithin a general zone Z₁ of potentially cancerous tissue surrounding theentire biopsy cavity BC (FIG. 12 b) or within a specific zone Z₂ locatedon only one side of the biopsy cavity BC (FIG. 12 c).

With specific reference to the showing of FIG. 12 b, the removal of alltissue within a general zone Z₁ surrounding the entire biopsy cavity BCmay be desirable in cases where the pathology report has indicated thatthe previously removed biopsy specimen had no clear margin and, thus, itis desirable to remove all tissue within the zone Z₁ of width Xsurrounding the biopsy cavity BC on all sides.

With specific reference to the showing of FIG. 12 c, the removal ofcertain tissue within a specific zone Z₂ located to one side of an axisthat has been projected throughout the biopsy cavity BC may be desirablein cases where the pathology report has indicated that the previouslyremoved biopsy specimen had clear margins on all but one side and, thus,it is desirable to remove only tissue that is located within thespecific zone Z₁ of width X on one side of the biopsy cavity BC.

The invention has been described hereabove with reference to certainpresently preferred embodiments, and no attempt has been made todescribe all possible embodiments in which the invention may takephysical form. Indeed, numerous modifications, additions, deletions andalterations may be made to the above-described embodiments withoutdeparting from the intended spirit and scope of the invention.Accordingly, it is intended that all such additions, deletions,modifications and alterations be included within the scope of thefollowing claims.

1. A target tissue localization device comprising: an elongate tubularmember having a proximal end, a distal end, and a lumen therebetween, aplurality of bioabsorbable bodies disposed in the lumen and at least oneof the bioresorbable bodies within the inner lumen having aradiographically detectable marker with a non-natural shape. 2-57.(canceled)
 58. A target tissue localization device comprising: anelongate tubular member having a proximal end, a distal end, and a lumentherebetween; a bioresorbable body contained within the elongate tubularmember, the bioresorbable body comprising gelatin; a radiographicallydetectable marker carried by the body.
 59. The target tissuelocalization device of claim 58, wherein the bioresorbable body isremotely visualizable by at least one of ultrasound and mammography. 60.The target tissue localization device of claim 58, wherein theradiopaque marker is contained within the bioresbrbable body.
 61. Thetarget tissue localization device of claim 58, wherein the bioresorbablebody comprises at least one bioresorbable body.
 62. The target tissuelocalization device of claim 58, wherein the bioresorbable body swellsupon contact with body fluid.
 63. The target tissue localization deviceof claim 5, wherein the bioresorbable body swells to substantially fillthe biopsy site.
 64. A method for marking a biopsy cavity comprising thesteps of: providing a bioresorbable body having a radiopaque markercarried by the bioresorbable body, said bioresorbable body comprisinggelatin; removing a biopsy specimen from the breast of a patient,thereby creating a biopsy site; inserting the bioresorbable body intothe biopsy site to mark the location of the biopsy site; and testing thebiopsy specimen.
 65. The method of claim 64, further comprising the stepof relocating the biopsy site by detecting the radiopaque marker. 66.The method of claim 64, wherein the bioresorbable body comprises atleast one bioresorbable body.
 67. The method of claim 64, wherein theradiopaque marker is contained within the bioresorbable body.
 68. Themethod of claim 65, wherein the radiopaque marker is detected bymammography.
 69. The method of claim 65, wherein the radiopaque markeris detected by ultrasound.
 70. The method of claim 64, wherein thebioresorbable body swells upon contact with body fluid.
 71. The methodof claim 64, wherein the bioresorbable body swells to substantially fillthe biopsy site.
 72. A target tissue localization device comprising: anelongate tubular member having a proximal end, a distal end, and a lumentherebetween; a bioresorbable body contained within the elongate tubularmember, the bioresorbable body comprising polylactic acid; and aradiopaque marker carried by the bioresorbable body.
 73. The targettissue localization device of claim 72, wherein the bioresorbable bodyfurther comprises polyglycolic acid.
 74. A method for marking a biopsycavity comprising the steps of: providing a bioresorbable body having aradiopaque marker carried by the bioresorbable body, said bioresorbablebody comprising polylactic acid; removing a biopsy specimen from thebreast of a patient, thereby creating a biopsy site; inserting thebioresorbable body into the biopsy site to mark the location of thebiopsy site; and testing the biopsy specimen.
 75. The method of claim74, wherein the bioresorbable body further comprises polyglycolic acid.76. A target tissue localization device comprising: an elongate tubularmember having a proximal end, a distal end, and a lumen therebetween; abioresorbable body contained within the elongate tubular member, thebioresorbable body comprising polyglycolic acid; and a radiopaque markercarried by the bioresorbable body.
 77. A method for marking a biopsycavity comprising the steps of: providing a bioresorbable body having aradiopaque marker carried by the bioresorbable body, said bioresorbablebody comprising polyglycolic acid; removing a biopsy specimen from thebreast of a patient, thereby creating a biopsy site; inserting thebioresorbable body into the biopsy site to mark the location of thebiopsy site; and testing the biopsy specimen.
 78. An intracorporeal sitemarker for marking a selected site within tissue of a patient's body,comprising: (a) an ultrasound detectable body including boundarieshaving a high contrast in acoustical impedance when the marker is placedin tissue of the selected site, so as to efficiently reflect ultrasoundduring ultrasound imaging; and (b) a body shape which is recognizablyartificial when the marker is subject to ultrasound or X-ray imaging, soas to be readily distinguishable from biological features within thetissue site.
 79. A remotely imageable marker for marking a selectedintracorporeal site within a patient, comprising: (a) an ultrasounddetectable body; and (b) a radiopaque marker element carried by theultrasound detectable body on an exterior portion thereof.
 80. Theremotely imageable marker of claim 79, wherein the ultrasound detectablebody is formed at least in part of a material selected from the groupconsisting of gelatin, collagen, cross-linked collagen, polymericmaterial, and mixtures and composites thereof.
 81. The remotelyimageable marker of claim 79, wherein the radiopaque marker element is ametallic band disposed at least partially surrounding the ultrasounddetectable body.
 82. The remotely imageable marker of claim 81, whereinthe metallic band is recognizably artificial when the marker is subjectto ultrasound or X-ray imaging, so as to be readily distinguishable frombiological features within the tissue site.
 83. A method of marking aselected intracorporeal tissue site for subsequent location, comprising:(a) providing at least one marker having an ultrasound detectable bodyand a radiopaque marker element carried by the ultrasound detectablebody on an exterior portion thereof; and (b) implanting the marker at apreselected target site, so that the body is detectable when subject toultrasound imaging.
 84. The method of claim 83, wherein implanting atleast one marker includes inserting the marker through a biopsy needledevice which has been previously inserted into the tissue site in thecourse of a biopsy procedure.
 85. The method of claim 84, whereininserting the at least one marker through a biopsy needle deviceincludes: (a) using a vacuum-assisted large core biopsy device as thebiopsy needle device; and (b) the insertion of the marker includes: (i)loading the marker into a marker applicator device having an elongatedmarker insertion tube for holding the marker, the tube having a distaltip and a piston housed within the tube for expelling the marker fromthe tip; (ii) inserting the marker insertion tube through the large corebiopsy device until the tip is adjacent the tissue site; and (iii)depressing the piston to expel the at least one marker from the tube toimplant adjacent the tissue site.